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Autosomal recessive mitochondrial ataxic syndrome due to mitochondrial polymerase mutations

From the Departments of Neurology (S. Winterthun and Drs. Engelsen and Bindoff) and Radiology (Dr. Moen), Haukeland University Hospital, University of Bergen, Norway; Unit of Molecular Neurogenetics Pierfranco and Luisa Mariani Center for the Study of Children's Mitochondrial Disorders (G. Ferrari and Dr. Zeviani), National Neurological Institute "C. Besta", Milan, Italy; and Mitochondrial Research Group (Drs. He, Taylor, and Turnbull), School of Neurology, Neurobiology and Psychiatry, The Medical School, University of Newcastle upon Tyne, UK.

Address correspondence and reprint requests to Professor Laurence Bindoff, Department of Neurology, Institute of Clinical Medicine and Molecular Medicine, University of Bergen, Haukeland University Hospital, 5021 Bergen, Norway; e-mail: laurence.bindoff{at}nevro.uib.no

Objective: To investigate three families and one sporadic case with a recessively inherited ataxic syndrome.

Methods: Clinical and genetic studies were performed in six individuals. Southern blotting and real time PCR were used to detect deletions of mtDNA and mutations in the POLG gene were identified using a combination of DHPLC and direct DNA sequencing.

Results: The patients have a distinctive, progressive disorder that starts with episodic symptoms such as migraine-like headache or epilepsy. Ataxia, which is a combination of central and peripheral disease, develops later as does ophthalmoplegia. The commonest form of epilepsy was focal and involved the occipital lobes. Myoclonus was common and patients have a high risk of status epilepticus. MRI typically shows signal changes in the central cerebellum, olivary nuclei, occipital cortex, and thalami. COX negative muscle fibers were found in four of six; in one patient these were rare and in another absent. Multiple mtDNA deletions were identified in all patients, although in two these were not apparent on Southern blotting and real time PCR was required to demonstrate the defect. Two families were homozygous for a previously described POLG mutation, G1399A (A467T). One family and the sporadic case had the same two new mutations, a G to C at position 1491 (Q497H) and a G to C at 2243 (W748S).

Conclusions: Mutations in POLG cause a recessively inherited syndrome with episodic features and progressive ataxia. Characteristic changes on MRI are seen and although skeletal muscle may appear morphologically normal, multiple mtDNA deletions can be detected using real-time PCR.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the April 12 issue to find the title link for this article.

*These authors contributed equally to this work.

Supported by L. Meltzer Høyskolefond (project number 480210) and Helse Vest (L.A.B., S.W.); Wellcome Trust, Muscular Dystrophy Campaign and Newcastle upon Tyne Hospitals NHS Trust (R.W.T., D.M.T.); Fondazione Telethon-Italy (grant n. GGP030039 to M.Z.); Fondazione Pierfranco e Luisa Mariani (Ricerca 2000 to M.Z.); Ricerca Finalizzata Ministero della Salute RF-2002/158 (to M.Z.); Fondazione Cariplo (to M.Z.); and MitEuro network grant from the European Union Framework Program 5 (to M.Z., L.A.B.).

Received June 30, 2004. Accepted in final form December 13, 2004.

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